Physiological roles of placental proteases in feto-placental homeostasis.

Although many proteases exist in human placenta, their physiological roles are still largely unknown. Our studies showed that these placental proteases metabolize vasoactive and immunomodulating peptides, possibly derived from the fetus, and control the exchange of peptide hormones across the placenta in order to maintain feto-placental homeostasis. We clarified the pregnancy serum oxytocinase discovered by Fekete in 1930 and angiotensinase by Page in 1947, respectively. In addition we showed bradykininase in the pregnancy serum. The ratio of peak systolic over least diastolic flow velocity of uterine or umbilical artery assessed by the Doppler technique was closely correlated with the levels of maternal serum proteases in preeclampsia, which suggested that placental proteases might control uteroplacental circulation via the regulation of concentrations of vasoactive peptides in uteroplacental circulation. Thus, changes in maternal serum protease activities were useful for monitoring of pre-elcampsia and predicting the onset of labor. The degradation of immunomodulating peptides by placental protease(s) also suggests the possible involvement of placental protease(s) in the immunological aspect of pregnancy. Recently we have cloned one of the major placental protease, oxytocinase (P-LAP). Its amino acid sequences had 87% homology of rat IRAP so called VP 165. This enzyme was confirmed to co-localize in Glut 4 containing vesicles in rat skeletal muscles and adipocytes. Accordingly PLAP, the human homologue of VP165, may have an intriguing possibility in a variety of events not restricted to the regulation of pregnancy induced phenomena.